Helena Brentanihelena.brentani@gmail.com

Fetal origins of mental health: Evidence and mechanisms

Wolff Schlotz a,*, David I.W. Phillips

Brain, Behavior, and Immunity 23 (2009) 905–916

GestationBirth

ProdromicBeginningChronicityDeterioration

10 20 30 40 50Years

Puberty

Premorbid

Brain abnormal development Neurochemistryimba

lance

Irreversiblemodifications

Mediatorsofneurotoxicity:

•Neurotrophins

•Inflammation

•Oxidative stress

Liebermanet al., BiolPsychiatry2001

Developmental trajectories of mental disorders

1. Introdução

Intervention

Learning, memory,

impulse

control

Enviroment

Perception, cognition

Genes, cells, imaging studies

Biological MarkersBiological Markers

Searching for early diagnosisSearching for early diagnosis

① Is it possible to predict who will develop neurodevelopmentdisorders ? 

① Is it possible to predict who will develop neurodevelopmentdisorders ? 

② Is genomic instability different betweenneurodevelopment disorders cases vs controls?

② Is genomic instability different betweenneurodevelopment disorders cases vs controls?

③ Is the neuron diferentiation transcriptome fromcases different from controls?

③ Is the neuron diferentiation transcriptome fromcases different from controls?

Schizophrenia is a neurodevelopment disorder

Yamanaka, 2009.

The best way to study neurodevelopment disordersis with Induced Pluripotent Stem Cells ‐ iPS

Using skin fibroblast from cases and controls we recapituledthe neuron diferentiation

Neurons from schizophrenic presented more ROS and

extramitochondrial O2 consumption

Using microarrays to compare NPCcontrol X ips control

and NPCschizo X ipsschizo

Down-regulated genesVenn-diagram

Up-regulated genes

741957 77 6011057 151

228 genes differentially expressed

in schizophrenia during neuro diferentiation

Control Schizophrenic Control Schizophrenic

Comparing one region of the frontal lobe from brain tissue from Stanley

Foundation (25 schizo X 25 controls) we found 637 genes differentially

expressed

We searched the 228 differentially expressed genes in schizophrenia during

neuron diferentiation (ips-NPC) in the Stanley arrays. We could observe that the

coexpression of some gene pairs has changed from controls to cases

Node Class Degree in_list

RB1 HubBroker 155Yes

JUN Hub 55 No

B2M HubBroker 58 Yes

FOS HubBroker 126Yes

CREBBP Hub 50 No

BRCA1 Hub 51 No

EP300 Hub 56 No

ESR1 HubBroker 79 No

TP53 HubBroker 65 No

RELA Hub 51 No

MYC Hub 60 No

SP1 Hub 50 No

Comparing 228 genes from ips/NPC with 637 genes differentially expressed

in stanley frontal lobe from casesxcontrols we found 33 comonly differentially

expressed= Using the human interactome we can found brokers and hubs in

the network: tumor supressors and oncogenes

22schools in Porto Alegre

35schools in São Paulo

São Paulo andPorto Alegre 

Screeningof9.937Childrenform6 to 12 yearsold

To detect predictors of normal and abnormal mental and behavior development in a scholar sample of 6 to 12 years old children.

To refine the concept of “at‐risk” for mental disorders from clinical, neuropsychological, genetic and neuroimaging perspectives.

Scholar High risk cohort study – PREVENTION Study fromNational Institute of Development Psychiatry (INPD)

Scholar High risk cohort study – PREVENTION Study fromNational Institute of Development Psychiatry (INPD)

Parental  interviews

Scholar evaluations

Samples colected

2 500

INPD

USP: EuripedesConstantino Miguel, RoseliShavitt, SilvanaChiavegatto, BacyBylik

UFRGS: Luis Augusto Rohde, Gisele Manfro

UNIFESP: Marcos Mercadantes, Rodrigo Bressan, Maria Conceição do Rosário

UFPE: MagdalaNovaes

kkkk

UFBA: Irismar Oliveira, AlineSampaio

INPD Team

Dr Stevens Reins CNPQ